The body is composed of various tissue microenvironments with finely tuned local immunosurveillance systems, many of which are in close apposition with distinct commensal niches. Mammals have formed ...an evolutionary partnership with the microbiota that is critical for metabolism, tissue development and host defense. Despite our growing understanding of the impact of this host-microbe alliance on immunity in the gastrointestinal tract, the extent to which individual microenvironments are controlled by resident microbiota remains unclear. In this Perspective, we discuss how resident commensals outside the gastrointestinal tract can control unique physiological niches and the potential implications of the dialog between these commensals and the host for the establishment of immune homeostasis, protective responses and tissue pathology.
Epidermal stem cells “remember” inflammation, accelerating subsequent wound repair
Our body's epithelia are barriers that interface with the terrestrial environment and routinely experience ...inflammation. Although a vast majority of these inflammatory reactions resolve, they imprint the tissue with a memory. Cells of the immune system are traditionally thought to be the bearers of this memory, allowing them to react faster to subsequent inflammatory pressures (
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). Yet, barrier tissues are composites of epithelial, mesenchymal, nervous, vascular, and immunological networks working in unison to sustain optimal function in health and disease. The question of whether tissue-resident cells, distinct from the immune system, are entrained in response to a perturbation remains to be addressed.
The skin interfaces with the external environment and is home to a myriad of immune cells that patrol the barrier to ward off harmful agents and aid in tissue repair. The formation of the cutaneous ...immune arsenal begins before birth and evolves throughout our lifetime, incorporating exogenous cues from microbes and inflammatory encounters, to achieve optimal fitness and function. Here, we discuss the context-specific signals that drive productive immune responses in the skin epithelium, highlighting key modulators of these reactions, including hair follicles, neurons, and commensal microbes. We thus also discuss the causal and mechanistic underpinning of inflammatory skin diseases that have been revealed in recent years. Finally, we discuss the non-canonical functions of cutaneous immune cells including their burgeoning role in epithelial regeneration and repair. The rapidly growing field of cutaneous immunity is revealing immune mechanisms and functions that can be harnessed to boost skin health and treat disease.
Kobayashi, Naik, and Nagao discuss recent findings on skin immunity that highlight that the skin immune system is maintained through intricate crosstalk between the parenchyma, immune cells, and microbiota, all of which are crucial components for boosting healthy skin function and driving pathology in disease.
Stem cells regenerate tissues in homeostasis and under stress. By taking cues from their microenvironment or “niche,” they smoothly transition between these states. Immune cells have surfaced as ...prominent members of stem cell niches across the body. Here, we draw parallels between different stem cell niches to explore the context-specific interactions that stem cells have with tissue-resident and recruited immune cells. We also highlight stem cells’ innate ability to sense and respond to stress and the enduring memory that forms from such encounters. This fascinating crosstalk holds great promise for novel therapies in inflammatory diseases and regenerative medicine.
Understanding the crosstalk between immune and stem cells under homeostatic conditions provides insights into our understanding of inflammatory disease.
The skin barrier is the body's first line of defence against environmental assaults, and is maintained by epithelial stem cells (EpSCs). Despite the vulnerability of EpSCs to inflammatory pressures, ...neither the primary response to inflammation nor its enduring consequences are well understood. Here we report a prolonged memory to acute inflammation that enables mouse EpSCs to hasten barrier restoration after subsequent tissue damage. This functional adaptation does not require skin-resident macrophages or T cells. Instead, EpSCs maintain chromosomal accessibility at key stress response genes that are activated by the primary stimulus. Upon a secondary challenge, genes governed by these domains are transcribed rapidly. Fuelling this memory is Aim2, which encodes an activator of the inflammasome. The absence of AIM2 or its downstream effectors, caspase-1 and interleukin-1β, erases the ability of EpSCs to recollect inflammation. Although EpSCs benefit from inflammatory tuning by heightening their responsiveness to subsequent stressors, this enhanced sensitivity probably increases their susceptibility to autoimmune and hyperproliferative disorders, including cancer.
Electrophysiology recordings are frequently affected by artifacts (e.g., subject motion or eye movements), which reduces the number of available trials and affects the statistical power. When ...artifacts are unavoidable and data are scarce, signal reconstruction algorithms that allow for the retention of sufficient trials become crucial. Here, we present one such algorithm that makes use of large spatiotemporal correlations in neural signals and solves the low-rank matrix completion problem, to fix artifactual entries. The method uses a gradient descent algorithm in lower dimensions to learn the missing entries and provide faithful reconstruction of signals. We carried out numerical simulations to benchmark the method and estimate optimal hyperparameters for actual EEG data. The fidelity of reconstruction was assessed by detecting event-related potentials (ERP) from a highly artifacted EEG time series from human infants. The proposed method significantly improved the standardized error of the mean in ERP group analysis and a between-trial variability analysis compared to a state-of-the-art interpolation technique. This improvement increased the statistical power and revealed significant effects that would have been deemed insignificant without reconstruction. The method can be applied to any time-continuous neural signal where artifacts are sparse and spread out across epochs and channels, increasing data retention and statistical power.
Caloric restriction is known to improve inflammatory and autoimmune diseases. However, the mechanisms by which reduced caloric intake modulates inflammation are poorly understood. Here we show that ...short-term fasting reduced monocyte metabolic and inflammatory activity and drastically reduced the number of circulating monocytes. Regulation of peripheral monocyte numbers was dependent on dietary glucose and protein levels. Specifically, we found that activation of the low-energy sensor 5′-AMP-activated protein kinase (AMPK) in hepatocytes and suppression of systemic CCL2 production by peroxisome proliferator-activator receptor alpha (PPARα) reduced monocyte mobilization from the bone marrow. Importantly, we show that fasting improves chronic inflammatory diseases without compromising monocyte emergency mobilization during acute infectious inflammation and tissue repair. These results reveal that caloric intake and liver energy sensors dictate the blood and tissue immune tone and link dietary habits to inflammatory disease outcome.
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•Fasting reduces the numbers of circulating monocytes in healthy humans and mice•Fasting also reduces monocyte metabolic and inflammatory activity•Hepatic energy-sensing regulates homeostatic monocyte numbers via CCL2 production•Fasting improves inflammatory diseases without compromising antimicrobial immunity
Caloric restriction reduces the number of circulating inflammatory monocytes in a CCL2/PPARa-dependent manner, without compromising responses to acute inflammation.
The gut microbiota influences both local and systemic inflammation. Inflammation contributes to development, progression, and treatment of cancer, but it remains unclear whether commensal bacteria ...affect inflammation in the sterile tumor microenvironment. Here, we show that disruption of the microbiota impairs the response of subcutaneous tumors to CpG-oligonucleotide immunotherapy and platinum chemotherapy. In antibiotics-treated or germ-free mice, tumor-infiltrating myeloid-derived cells responded poorly to therapy, resulting in lower cytokine production and tumor necrosis after CpG-oligonucleotide treatment and deficient production of reactive oxygen species and cytotoxicity after chemotherapy. Thus, optimal responses to cancer therapy require an intact commensal microbiota that mediates its effects by modulating myeloid-derived cell functions in the tumor microenvironment. These findings underscore the importance of the microbiota in the outcome of disease treatment.
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